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Hepatocyte nuclear factor-1? regulates Wnt signaling through genome-wide competition with ?-catenin/lymphoid enhancer binding factor.

ABSTRACT: Hepatocyte nuclear factor-1? (HNF-1?) is a tissue-specific transcription factor that is essential for normal kidney development and renal tubular function. Mutations of HNF-1? produce cystic kidney disease, a phenotype associated with deregulation of canonical (?-catenin-dependent) Wnt signaling. Here, we show that ablation of HNF-1? in mIMCD3 renal epithelial cells produces hyperresponsiveness to Wnt ligands and increases expression of Wnt target genes, including Axin2, Ccdc80, and Rnf43 Levels of ?-catenin and expression of Wnt target genes are also increased in HNF-1? mutant mouse kidneys. Genome-wide chromatin immunoprecipitation sequencing (ChIP-seq) in wild-type and mutant cells showed that ablation of HNF-1? increases by 6-fold the number of sites on chromatin that are occupied by ?-catenin. Remarkably, 50% of the sites that are occupied by ?-catenin in HNF-1? mutant cells colocalize with HNF-1?-occupied sites in wild-type cells, indicating widespread reciprocal binding. We found that the Wnt target genes Ccdc80 and Rnf43 contain a composite DNA element comprising a ?-catenin/lymphoid enhancer binding factor (LEF) site overlapping with an HNF-1? half-site. HNF-1? and ?-catenin/LEF compete for binding to this element, and thereby HNF-1? inhibits ?-catenin-dependent transcription. Collectively, these studies reveal a mechanism whereby a transcription factor constrains canonical Wnt signaling through direct inhibition of ?-catenin/LEF chromatin binding.

SUBMITTER: Chan SC

PROVIDER: S-EPMC6883834 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Hepatocyte nuclear factor-1β regulates Wnt signaling through genome-wide competition with β-catenin/lymphoid enhancer binding factor.

Chan Siu Chiu SC Zhang Ying Y Pontoglio Marco M Igarashi Peter P

Proceedings of the National Academy of Sciences of the United States of America 20191111 48

Hepatocyte nuclear factor-1β (HNF-1β) is a tissue-specific transcription factor that is essential for normal kidney development and renal tubular function. Mutations of HNF-1β produce cystic kidney disease, a phenotype associated with deregulation of canonical (β-catenin-dependent) Wnt signaling. Here, we show that ablation of HNF-1β in mIMCD3 renal epithelial cells produces hyperresponsiveness to Wnt ligands and increases expression of Wnt target genes, including <i>Axin2</i>, <i>Ccdc80</i>, an ...[more]

PMID: 31712448

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Project description:The sensitization of hepatocytes to cell death from tumor necrosis factor ? (TNF?) underlies many forms of hepatic injury, including that from toxins. Critical for hepatocyte resistance to TNF? toxicity is activation of nuclear factor ?B (NF-?B) signaling, which prevents TNF?-induced death by the up-regulation of protective proteins. To further define the mechanisms of hepatocyte sensitization to TNF? killing, immunoblot analysis comparing livers from mice treated with lipopolysaccharide (LPS) alone or LPS together with the hepatotoxin galactosamine (GalN) was performed to identify TNF?-induced protective proteins blocked by GalN. Levels of CCAAT/enhancer-binding protein ? (C/EBP?) were increased after LPS treatment but not GalN/LPS treatment. In a nontransformed rat hepatocyte cell line, TNF?-induced increases in C/EBP? protein levels were dependent on NF-?B-mediated inhibition of proteasomal degradation. Pharmacological inhibition of c-Jun N-terminal kinase (JNK) did not affect C/EBP? degradation, indicating that the process was JNK-independent. C/EBP? functioned to prevent cell death as adenoviral C/EBP? overexpression blocked TNF?-induced apoptosis in cells sensitized to TNF? toxicity by NF-?B inhibition. C/EBP? inhibited TNF?-induced caspase 8 activation and downstream mitochondrial cytochrome c release and caspase 3 and caspase 7 activation. Studies in primary hepatocytes from c/ebp?(-/-) mice confirmed that loss of C/EBP? increased death from TNF?. c/ebp?(-/-) mice were also sensitized to liver injury from a nontoxic dose of LPS or TNF?. The absence of jnk2 failed to reverse the GalN-induced block in C/EBP? induction by LPS, again demonstrating that C/EBP? degradation was JNK-independent.C/EBP? is up-regulated by TNF? and mediates hepatocyte resistance to TNF? toxicity by inhibiting caspase-dependent apoptosis. In the absence of NF-?B signaling, proteasomal degradation of C/EBP? is increased by a JNK-independent mechanism and promotes death from TNF?.

Dataset Information

Hepatocyte nuclear factor-1? regulates Wnt signaling through genome-wide competition with ?-catenin/lymphoid enhancer binding factor.

Publications

Hepatocyte nuclear factor-1β regulates Wnt signaling through genome-wide competition with β-catenin/lymphoid enhancer binding factor.

Similar Datasets

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